3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester → 5-amino-2-(2,6-difluorophenyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide

Participants

Reaction Conditions

Reaction Steps

A mixture of tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (234 mg, 0.5 mmol), potassium fluoride dihydrate (155 mg, 1.65 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol) in THF (5 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2, 60 mg, 0.05 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 110° C. for 8 hr. Water (10 mL) was added and the mixture extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel chromatography (isohexane then 0-5% MeOH/EtOAc). The resulting intermediate was dissolved in MeOH (5 mL) and treated with a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 16 hr and the solvent removed under reduced pressure. Purification via preparative HPLC gave 101 as a brown solid (37 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.05 (s, 1H), 7.38-7.26 (m, 1H), 7.06-6.97 (m, 2H), 6.13 (s, 2H), 6.03-6.00 (m, 1H), 4.41 (d, J=2.8 Hz, 1H), 4.39 (d, J=2.8 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 2.45-2.41 (m, 2H). LCMS (ES+) m/z 418 (M+1).

Provenance & Evidence